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an online version of the magazine Winter 2005
Medical Rounds
Linzhao Cheng, building better stem cells.
Linzhao Cheng, buiding better stem cells.


Building Better Stem Cells: Linzhao Cheng

The cellular biologist Linzhao Cheng has set out to overcome some of the more challenging technical problems standing in the way of using stem cells to treat disease. “Good ideas come from bad experiences,” he says.

Cheng returned to Hopkins five years ago to take a faculty position, after getting his Ph.D. here and then spending four years in industry solving stem-cell-related problems. And 2003 was a very good year for him.

He earned a Presidential Early Career Award for Scientists and Engineers, and then was invited to join the Program in Stem Cell Research at Hopkins ' elite Institute for Cell Engineering. Since then, his band of researchers has devised several technologies for introducing genes into human stem cells. They've also come up with a safer method for growing those cells.

That second contribution sprang from the fact that researchers struggling to keep human cells alive were using cultures made up of mouse “feeder” cells, a practice that posed certain risks. It could, for example, expose the human stem cells to new viruses that could be passed on to patients. The team figured out a way to provide the same survival signals the mouse cells emitted using human feeder cells to grow the stem cells. Now, when and if government regulations allow new cell lines to be created, scientists will have a more risk-free method in hand.

Most recently, Cheng has tackled the problem of stem-cell rejection. Because our bodies view stem cells as different from the cells that normally populate our various organs, our immune systems respond by attacking the stem cells. But one particular group of immune cells, antigen-presenting cells, controls whether or not that attack is mounted. This year, Cheng set out to create antigen-presenting cells from human stem cells. This, he conjectured, would give him a device for signaling the immune system to ignore those unfamiliar therapeutic stem cells. So far, he's gotten by the first hurdle—he's been able to make antigen-presenting cells. Now, he's moving on to step two: preventing the immune response to stem cells. Stay tuned.


Daphne Monie


Consultation with Connie Trimble

Connie Trimble

The director of the Cervical Dysplasia Center talks about the vaccine that could stop human papillomavirus infection from turning into cervical cancer—the second leading cause of cancer death in women.


Even when cancer vaccines have shown promise in mice, they've seldom panned out in humans. What's different about the HPV vaccine you're working on?


Most therapeutic vaccines have been tested only in people who've already tried every other treatment option. But by then, they're so sick that their immune systems can't really respond to the vaccines. We're testing our vaccine in otherwise healthy women who are positive for HPV 16, the virus type that's found in more than half of all cervical cancers and also in the lesions that occur before cancer develops. Our vaccine—it's taken 10 years to develop!—helps the body launch an immune response that nails the infected cells.


You've seen that happen in lab animals, of course, but if a woman has an abnormal Pap smear, don't you have to remove the abnormality immediately? Can you really afford to wait to see if the vaccine triggers a human being's immune system?


Before we started the phase I clinical trial, we carefully observed nearly 200 volunteers who all had precancerous lesions. They were angels—they weren't getting vaccine; they had nothing to gain. They agreed to let us follow them for 15 weeks before we removed their lesions. During this time, we not only found that no one's lesion got worse, but in about a third of the women, the lesions actually went away on their own, without any treatment. Isn't that wild? Their immune systems were doing what we want the vaccine to do. So, now we're in position to find out how the vaccine works, not in the lab, but in people who are “ready” to be cured.


And that's important because?


People are messy, gregarious creatures. We all have different genetic and environmental backgrounds. You can't assume that our patients are gonna behave like 70-kilogram lab mice that all have the same genetic background, the exact same tumor. In the end, it doesn't really matter what happens in a mouse; it matters what happens in people. There is a huge rate of cervical cancer, particularly here in Baltimore , and our best chances of curing this disease are in its pre-cancerous stages. That's what this vaccine is all about.


Belzberg Saves a Youthful Leg

Allan Belzberg did a daring sciatic nerve repair on Derrick Goodrich.
> Allan Belzberg did a daring sciatic nerve repair on Derrick Goodrich.

Last April, two weeks into his tour in Iraq near the Syrian border, 23-year-old Derrick Goodrich was hit by a bullet from close range. The accidental discharge from a gun behind him shattered his hip and vaporized five inches of his sciatic nerve. “They told me amputation and a prosthesis would make it easier for me to get around,” Goodrich says.

But the young soldier wanted a second opinion. And so it was that last November, Hopkins neurosurgeon Allan Belzberg decided to try an approach to save Goodrich's leg that may have been a first in the world. The peripheral technique he uses to repair nerves in the neck and arm, he postulated, might also work on the sciatic nerve.

The largest nerve in the body, the sciatic originates from lumbar and sacral spinal nerve offshoots that meet in one nerve sheath deep in the pelvis. “The pelvis is difficult real estate,” Belzberg says, “a tough area to expose. And going near the spinal cord puts the bladder and bowel function at risk.” Belzberg decided finally he'd bypass the nerve's natural pelvic route and connect one end of the repair graft to the nerves as they exit the spine and the other end to the uninjured part of the sciatic nerve.

Belzberg first freed the spinal cord from surrounding vertebral bone to gain access to the spinal nerves. Then, he threaded the sural nerve through a silicone tube from the incision near the spine to a second incision in the buttocks. Lastly, he pulled the tube out and attached the nerve's ends with something like super glue. An eight-hour surgery. Then they waited.

“One day, a few months later, I bumped my shin against a chair and, for the first time, I could feel it,” Goodrich says. Now he can stand and bend his leg. “Things look very promising,” Belzberg says.


Marjorie Centofanti

Meet Breast Surgeon Lisa Jacobs

Lisa Jacobs


Curiosity has repeatedly taken Lisa Jacobs to unexpected places. When she was a child growing up in a two-bedroom trailer on a remote pig farm in the middle of Missouri , her mother would cut up animal hearts for her 6-year-old daughter to inspect. It incited a lasting desire to study medicine. Jacobs first became a physical therapist, then entered medical school, intending to specialize in rehabilitation medicine. Instead, surgery drew her interest, and she decided to go into private practice. Then came her research year during residency, and she was sidelined yet again, accidently lighting upon some basic science research into breast cancer. Only then did a career in academic medicine seem evident.

In March, Jacobs joined the surgery faculty at Hopkins , where she is operating on breast cancer patients, setting up clinical research projects, including a study of patients with positive sentinel lymph nodes, and trying to establish a breast cancer database.

“When you do breast surgery, a lot of it is talking to women,” she says. “It's an hour long discussion about treatment choices—and answering more questions than you can imagine.”

Jacobs, who has two daughters, 4 and 1, has carved out a lifestyle that she hopes can serve as an example to women— and men—interested in pursuing surgery. “I can operate but still go home to be with my daughters. There are very few oncologic emergencies.”


Mary Ellen Miller

The Best Thing
I've Done In My Life

Jill Trimbath and Jennifer Axilbund help people at risk for cancer develop a plan.
> Jill Trimbath and Jennifer Axilbund help people at risk for cancer develop a plan.

When Dawn Koehler's gynecologist in Lebanon , Pa. , discovered a cyst on one of her ovaries, he asked for more information. Koehler, a 59-year-old nurse, had a family history of cancer, and her GYN wanted to know whether she, too, was at risk for developing a malignancy. With a simple blood sample, gene experts at the Johns Hopkins Cancer Risk Assessment Clinic would be able to tell her.

Luckily Koehler agreed to the two-hour trip to Baltimore , because, in the end, genetic testing achieved more than she'd expected. “It saved my life,” she says. The testing at Hopkins made clear that Koehler did indeed have a mutation on the BRCA1 gene, meaning her chances of developing ovarian cancer were more than 60 percent. Given a choice of options, she decided to act preventively and have both ovaries removed. But during surgery, her gynecologist struck a bombshell. Her left ovary already had a stage 2 cancer.

Ovarian cancer deserves its nickname, “the silent killer,” because it is rarely detected before stage 3 or stage 4, at which point it is usually too late to save the patient. In Koehler's case, her malignancy could be treated because it was found soon enough. She underwent six treatments of chemotherapy and today is back at work.

“Going through genetic testing is probably the best thing I've ever done in my life,” she says.


Michael Levin-Epstein

Removing a Horrendous Tumor in the Small Intestine

John Hill (with wife, Doris) is more than five years removed from his nine-hour surgery to get rid of duodenal cancer.
> John Hill (with wife, Doris) is more than five years removed from his nine-hour surgery to get rid of duodenal cancer.

Even six weeks after exploratory surgery for cancer of the small intestine, John Hill was still vomiting and losing weight. When two close friends—one a surgeon, the other a radiologist—recommended that he go to Johns Hopkins to be treated for his disease, John and his wife, Doris, drove from Buffalo, N.Y., to Baltimore with John's medical records in tow.

Their hopes were faint. “I thought we'd see the doctor for 15 minutes,” says Hill, 76, “and he'd tell me the same things”—that the tumor growing in his duodenum, near its connection to the stomach, was too entwined with the main blood vessels to be removed, and that radiation and chemotherapy were his only options.

Instead, when Mark Duncan at Johns Hopkins Bayview saw the scans the Hills had brought with them, he gave them unexpected news: “If I can get two fingers under that artery, I think I can get the tumor out.” Hill agreed immediately to the huge, nine-hour surgery, which took place in 1999.

This was not your average, run-of-the-mill case, Duncan says. “We didn't just take out the tumor in his duodenum. We had to remove the bypass where the stomach had been sewn to the intestine. We took out additional lymph nodes, a new mass that had developed, his gallbladder, a segment of his small bowel, a segment of his colon and part of the peritoneum. Plus, there was this scar tissue we had to get through from his initial operation. But we took a deep breath and just approached it systematically. Surgery is the cumulative effect of hundreds of tiny details.”

In the realm of cancer, Doris and John Hill knew that five years means a cure. Today, they have now passed that landmark. In the past year, they've traveled to China , Scotland and Ireland . And every summer they take their Buffalo friends who guided them to Hopkins to dinner, and they all raise a glass to Mark Duncan.


Mary Ellen Miller


More Sophisticated Pain Relief

Michael Erdek, the pain pro
> Michael Erdek, the pain pro

Conrad Potemra, a 55-year-old farmer in rural Poolesville , Md. , has learned something interesting about surgery: An operation can fail, but the outcome still can be successful. When Potemra had his spine operated on a couple of years ago to get rid of an ongoing inflammation from a granuloma, he knew his recovery might be difficult, but he had no idea how difficult.

First, doctors couldn't remove the tumor, and afterward Potemra couldn't even make it from his living room to the bathroom without a cane. To go back to work, he finally went on high doses of pain medication, but the effects of the drugs prevented him from doing even simple chores.

Then, in late 2003, Potemra's Hopkins neurologist, John Lattera, gave him a glimmer of hope. One of Lattera's colleagues, anesthesiologist Michael Erdek, had relieved pain in advanced-stage cancer patients by implanting a pump that allowed them to regulate their own medication.

Erdek, a specialist at the Blaustein Pain Center , explains this more-precise method this way: Patients who take medication orally or intravenously “often don't feel any better and wind up puking their guts out or wanting to sleep all day.” Instead of circulating through every single cell in the body and bombarding unaffected cells, with the pump, the drug goes directly to the root of the pain.

The procedure, however, is not cut and dried. Before a permanent pump is inserted, patients must spend several days in the hospital to determine the optimal level of their dosage and wean themselves from their oral medication. Also, a temporary catheter is used first to determine the dose that works best for that person.

But today, Potemra gets his permanent pump refilled only about every 100 days. And although he and Erdek still are trying to determine the optimal dosage, a microchip allows the delivery to be changed long distance. The happier farmer is back driving a tractor and operating a chain saw and says, “There's just no comparison in my quality of life.”


Michael Levin-Epstein

No Glamorous Calling

Jerry Lazarus at work
> Jerry Lazarus at work

Taking care of skin ulcers is no pretty business. Patients show up at the Center for Wound Healing at Johns Hopkins Bayview with gaping, raw holes in their legs or arms or midsections and in so much pain they can barely make it through the day. Sadly, though, as America 's aging population succumbs to illnesses like vascular disease and diabetes, knowing how to treat the often-accompanying chronic wounds becomes crucial. (The foot ulcers that plague diabetics alone result in 86,000 amputations a year.)

“This is really a lousy disease,” says Gerald Lazarus, the dermatologist who directs the Hopkins center. “Healthy people don't have chronic wounds. A doctor may be able to heal up a hole, but no one can get these patients functional again until the underlying etiology is addressed.” Dressing, cleaning and re-dressing open, running sores makes for lengthy exams. And even when a wound finally clears with antibiotics, support stockings or sophisticated dressings, patients can appear back in a few months, with the same symptoms.

And therein lies the kernel of why 65-year-old Lazarus, a former chairman and dean, chose to end his career in this out-of-the-way specialty. “Seeing that people get the care they need,” he says, “well, that's what this business is about. That and helping bright young people learn a field that's really important.”

For Lazarus, that hasn't meant straying into unknown territory. As chairman of dermatology at the University of Pennsylvania in the 1980s, he launched one of the first wound care centers in the country. By the 1990s, though, he'd been named dean of the School of Medicine at UC Davis and CEO of a $750 million health system. Then, in 2002, he and his wife settled on Maryland 's Eastern Shore, and Lazarus “gave Hopkins a call. They said, Sure, come on over, and we'll find something for you to do,” he says drolly. That something turned out to be the Center.

The eight-year-old Center had 5,000 patient visits in 2004. By 2006, Lazarus predicts that number will be up to 8,000. The facility prides itself on its dozen faculty physician consultants and a team of nurses that connects with even the most socially isolated of patients, hooking them up with critical services like home care. (“It sounds hokey, but it's really true,” Lazarus says. “This is nursing like it used to be.”)

The facility brings a solidly scientific approach to a field where care often is backed only by anecdotal evidence. It tracks the results of each new approach and uses a recently installed digital photography system to take detailed measurements of a wound's healing progress. “There are a million and one dressings available,” Lazarus says, “and a zillion new treatments like growth factors, immune modulators, expensive topical and systemic antibiotics. We're determined to find out what really works.”


Jim Duffy

Eyeballing Eyes

Are most diabetics getting the eye exams they need? No, says Ran Zeimer, director of the Ophthalmic Physics Laboratory at Johns Hopkins' Wilmer Eye Institute. Diabetic retinopathy is the leading cause of blindness among adults in the United States , but more than half of those with the disease don't receive the recommended eye exams. The screenings are especially important, Zeimer emphasizes, because vision loss can be staved off when the faulty blood vessels and swelling retina that signal retinopathy are detected early enough.

Now, thanks to a device invented by Zeimer and tested in a study funded by Eyetel, for which Zeimer's a paid consultant, there's an easier way for primary care physicians to perform these tests. Called the DigiScope, the instrument takes images of the retina in just minutes as patients sit in front of the instrument's automated camera looking at a series of blinking lights. The images are then sent from the physician's office to a reading center for interpretation.

According to a study conducted at the Henry Ford Health System in Detroit , the camera is as effective in identifying potential blindness in diabetics as the “gold standard” technique of stereo photography of the back of the eye. Zeimer couldn't be more pleased. Both he and Hopkins stand to benefit if the DigiScope catches on.

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